Is MAPT p.Pro229Arg (c.686C>G) pathogenic?

MAPT p.Pro229Arg (c.686C>G) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0836); Absent from gnomAD v4.1.

How common is MAPT p.Pro229Arg (c.686C>G) in the general population?

MAPT p.Pro229Arg (c.686C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Pro229Arg (c.686C>G)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

MAPT p.Pro229Arg

c.686C>G · VCV4874943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.4	GERP 2.6
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	17.22	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P154R vs ClinVar P229R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPT
Protein: p.Pro229Arg
Coding: c.686C>G
MANE Select: NM_001377265
Type: single nucleotide variant
Location: chr17:45983265 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 154 UniProt numbering: the 'disordered' region

Full MAPT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPT c.1999-10G>T Pathogenic ★★ same type
MAPT c.2091+16C>T Pathogenic ★★ same type
MAPT c.2091+3G>A Pathogenic ★★ same type
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same type
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same type
MAPT p.Asn688= Pathogenic ★★ same type
MAPT p.Gln728His Pathogenic/Likely pathogenic ★★ ⚠ same type
MAPT p.Gly727Ser Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapt-p-pro229arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown